A new study in Down syndrome, shows that the third copy of chromosome 21 leads to a rearrangement of the 3-D configuration of the entire genome in a major cell type of the developing brain. The resulting disturbance in gene transcription and cell function is so similar to that seen in cellular senescence, or senescence, that the scientists leading the study found they could use antiaging drugs to correct it in cell cultures.
The study was published in stem cell cells This establishes aging as a potentially targeted mechanism for the future treatment of Down syndrome, said Hiroi Miharina, a new assistant professor at UCSD who led work as Alana’s senior fellow at the Alana Center for Down Syndrome at MIT.
“There is a genome-specific abnormality at the cell level that is independent of the gene’s dose response,” Miharina said. “It is a phenomenon very similar to what we observe in aging. This suggests that excessive aging in the developing brain caused by the third copy of chromosome 21 could be a major cause of the neurodevelopmental abnormalities seen in Down syndrome.”
Lead researcher Li-Huei Tsai said the study’s finding that neuronal progenitor cells (NPCs), which develop into key brain cells including neurons, have a presbyopia character is remarkable and new, but it has been proven by the team’s extensive work. for clarification. The mechanism underlying the effects of abnormal chromosome number, or aneuploidy, within the nucleus of cells.
“This study demonstrates the importance of asking fundamental questions about the mechanisms underlying neurological disorders,” said Tsai, professor of neuroscience and director of the Alana Center and the Becker Institute for Learning and Memory at MIT. “We did not start this work expecting to see aging as a translational feature of Down syndrome, but the data emerged from questioning how the presence of an extra chromosome affects the structure of all of a cell’s chromosomes during development.”
Changes at the genome level
Miharina and his colleagues spent years measuring differences between cultures of human cells that differed only by whether they had a third copy of chromosome 21. Volunteer-derived stem cells were cultured to transform them into non-playable characters. In both stem cells and NPCs, the team examined 3-D chromosome structure, many measures of DNA structure and interaction, gene accessibility and transcription, and gene expression. They also looked at the consequences of gene expression differences on important functions of these developmental cells, such as how successfully they reproduce and migrate in 3D brain tissue cultures. Stem cells were not particularly different, but the non-playable characters were significantly affected by the third copy of chromosome 21.
In general, the image that emerged in the NPCs was that having a third copy causes all of the other chromosomes to be squashed in, as opposed to when people in a crowded elevator have to narrow their position when someone else pushes it. The main effects of this “chromosomal introversion,” which were precisely measured in the study, are more genetic interactions within each chromosome and fewer interactions between them. These changes and differences in the composition of DNA within the cell nucleus lead to changes in how genes are transcribed and thus expressed, causing important differences in cell function that affect brain development.
Treated as aging
During the first two years when these data came out, the full significance of the genomic changes wasn’t clear, Miharina said, but then he read research showing very similar genomic rearrangements and transcription changes in senescent cells.
After verifying that Down syndrome cells do indeed carry such a similar signature of transcriptional differences, the team decided to test whether antiaging drugs could reverse the effects. They tested a combination of two: dasatinib and quercetin. The drugs not only improved the accessibility and transcription of genes, but also the migration and proliferation of cells.
However, the drugs have very significant side effects — dasatinib is only given to cancer patients when other treatments aren’t enough — so they’re not suitable for trying to interfere with brain development amid Down syndrome, Miharina said. Alternatively, the study result could serve as inspiration for the search for drugs that can have anti-aging effects with a safer profile.
Cell aging is a stress response to cells. Meanwhile, years of research by former MIT biology professor Angelica Amon, who co-directs the Alana Center with Tsai, has shown that aneuploidy is a major stressor for cells. Thus, the question raised by the new findings is whether the aging-like character in Down syndrome NPCs is indeed the result of aneuploidy stress, and if so, what exactly is that stress.
Another implication of the findings is how excessive aging of brain cells can affect people with Down syndrome later in life. The risk of developing Alzheimer’s disease is much higher at a very young age in the population with Down syndrome than in the general population. This is thought to be largely due to the presence of a major Alzheimer’s risk gene, APP, on chromosome 21, but the new tendency to age may also accelerate the progression of Alzheimer’s disease.
The Alana Foundation, LuMind Foundation, Burroughs Wellcome Fund, UNCF-Merck and the National Institutes of Health funded the research.